1. Field of the Invention
The present invention relates to 1,3-diazolino and 1,3-diazolidino heterocycle derivatives and their use in therapy, in particular their use as nitric oxide synthase inhibitors.
2. Related Art
It has been known since the early 1980""s that the vascular relaxation caused by acetylcholine is dependent on the presence of the vascular endothelium and this activity was ascribed to a labile humoral factor termed endothelium-derived relaxing factor (EDRF). The activity of nitric oxide (NO) as a vasodilator has been known for well over 100 years. In addition, NO is the active component of amylnitrite, glyceryltrinitrate and other nitrovasodilators. The recent identification of EDRF as NO has coincided with the discovery of a biochemical pathway by which NO is synthesized from the amino acid L-arginine by the enzyme NO synthase.
Nitric oxide is the endogenous stimulator of the soluble guanylate cyclase. In addition to endothelium-dependent relaxation, NO is involved in a number of biological actions including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system (see Moncada et al., Biochemical Pharmacology, 38, 1709-1715, 1989; Moncada et al., Pharmacological Reviews, 43, 109-142, 1991). Excess NO production appears to be involved in a number of pathological conditions, particularly conditions which involve systemic hypotension such as toxic shock, septic shock and therapy with certain cytokines (Kerwin et al., J. Medicinal Chemistry, 38, 4343-4362, 1995).
The synthesis of NO from L-arginine can be inhibited by the L-arginine analogue, L-N-monomethyl-arginine (L-NMMA) and the therapeutic use of L-NMMA for the treatment of toxic shock and other types of systemic hypotension has been proposed (WO 91/04024 and GB-A-2240041). The therapeutic use of certain other NO synthase inhibitors apart from L-NMMA for the same purpose has also been proposed in WO 91/04024 and in EP-A-0446699.
It has recently become apparent that there are at least three types of NO synthase as follows:
(i) a constitutive, Ca++/calmodulin dependent enzyme, located in the endothelium, that releases NO in response to receptor or physical stimulation.
(ii) a constitutive, Ca++/calmodulin dependent enzyme, located in the brain, that releases NO in response to receptor or physical stimulation.
(iii) a Ca++ independent enzyme which is induced after activation of vascular smooth muscle,macrophages, endothelial cells, and a number of other cells by endotoxin and cytokines. Once expressed this inducible NO synthase generates NO continuously for long periods.
The NO released by the two constitutive enzymes acts as a transduction mechanism underlying several physiological responses. The NO produced by the inducible enzyme is a cytotoxic molecule for tumor cells and invading microorganisms. It also appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, may result largely from the effects of NO synthesized by the inducible NO synthase (Knowles and Moncada, Biochem J., 298, 249-258, 1994 Billiar et al., Annals of Surgery, 221, 339-349, 1995; Davies et al., 1995)
There is also a growing body of evidence that NO may be involved in the degeneration of cartilage which takes place in certain conditions such as arthritis and it is also known that NO synthesis is increased in rheumatoid arthritis and in osteoarthritis (McInnes et al., J. Exp. Med, 184, 1519-1524, 1996; Sakurai et al., J. Clin. Investig., 96, 2357-2363, 1995). Accordingly, conditions in which there is an advantage in inhibiting NO production from L-arginine include autoimmune and/or inflammatory conditions affecting the joints, for example arthritis, and also inflammatory bowel disease, cardivascular ischemia, diabetes, congestive heart failure, myocarditis, atherosclerosis, migraine, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, asthma, bronchiectasis, hyperalgesia (allodynia), cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia (secondary to cardiac arrest), multiple sclerosis and other central nervous system disorders mediated by NO, for example Parkinson""s disease and Alzheimer""s disease, and other disorders mediated by No including opiate tolerance in patients needing protracted opiate analgesics, and benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behaviour, for example, nicotine and eating disorders (Kerwin et al., a. Medicinal Chemistry, 38, 4343-4362, 1995; Knowles and Moncada, Biochem J., 298, 249-258, 1994; Davies et al., 1995; Pfeilschifter et al., Cell Biology International, 20, 51-58, 1996).
Further conditions in which there is an advantage in inhibiting NO production from L-arginine include systemic hypotension associated with septic and/or toxic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short term immunosuppression in transplant therapy (E. Kelly et al., J. Partent. Ent. Nutri., 19, 234-238, 1995; S. Moncada and E. Higgs, FASEB J., 9, 1319-1330, 1995; R. G. Kilbourn et al, Crit. Care Med., 23, 1018-1024, 1995).
Some of the NO synthase inhibitors proposed for therapeutic use so far, and in particular L-NMMA, are non-selective; they inhibit both the constitutive and the inducible NO synthases. Use of such a non-selective NO synthase inhibitor requires that great care be taken in order to avoid the potentially serious consequences of over-inhibition of the constitutive NO-synthase including hypertension and possible thrombosis and tissue damage. In particular, in the case of the therapeutic use of L-NMMA for the treatment of toxic shock it has been recommended that the patient must be subject to continuous blood pressure monitoring throughout the treatment. Thus, while non-selective NO synthase inhibitors have therapeutic utility provided that appropriate precautions are taken, NO synthase inhibitors which are selective in the sense that they inhibit the inducible NO synthase to a considerably greater extent than the constitutive isoforms of NO synthase would be of even greater therapeutic benefit and easier to use (S. Moncada and E. Higgs, FASEB J., 9,1319-1330, 1995).
WO 96/35677, WO 96/33175, WO 96/15120, WO 95/11014, WO 95/11231, WO 95/25717, WO 95/24382, WO94/12165, WO94/14780, WO93/13055, EP0446699A1 and U.S. Pat. No. 5,132,453 disclose compounds that inhibit nitric oxide synthesis and preferentially inhibit the inducible isoform of nitric oxide synthase. The disclosures of which are hereby incorporated by reference in their entirety as if written herein.
In a broad aspect, the present invention is directed to inhibiting or modulating nitric oxide synthesis in a subject in need of such inhibition or modulation by administering a compound which preferentially inhibits or modulates the inducible isoform of nitric oxide synthase over a constitutive isoform of nitric oxide synthase. It is also an object of the present invention to lower nitric oxide levels in a subject in need of such lowering.
Compounds of the present invention are represented by the following chemical formula: 
and pharmaceutically acceptable salts, wherein:
A is O, S or NR, wherein:
R is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, alkylaryl, alkylheterocycle, all optionally substituted by one or more of alkyl, hydroxy, alkoxy, halogen, haloalkyl, cyano, amino, and nitro; or
NR together form a heterocycle;
R1 is not present or is selected-from the group consisting of hydrogen, lower alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocycle, aryl, alkylaryl, and alkylheterocycle, all optionally substituted by one or more of alkyl, hydroxy, alkoxy, halogen, haloalkyl, cyano, amino, and nitro;
R2 is selected from the group consisting of amino, thioalkoxy, alkoxy, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, aryl, heterocycle, alkylaryl, alkylheterocycle, alkoxyalkyl, and thioalkoxyalkyl all optionally substituted by one or more of alkyl, hydroxy, alkoxy, halogen, haloalkyl, cyano, amino, and nitro;
R3 is not present or is selected from the group consisting of H, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycle, alkylaryl, and alkylheterocycle, all optionally substituted by one or more of halogen, haloalkyl, cyano, nitro, xe2x80x94CO2R, and xe2x80x94COR; or
R3 is selected from the group consisting of alkylhydroxy, alkylpolyhydroxy, alkyl(poly)oxyatcyl, CH2C(xe2x95x90O)OR6, CH2C(xe2x95x90O)NHR6, CH2OC(xe2x95x90O)R6, and CH2OC(xe2x95x90O)JR6, the CH2 is optionally substituted by one or more of lower alkyl, cycloalkyl, heterocycle, aryl, amidino, guanidino, CO2H, amino, hydroxy, thiol, halogen, haloalkyl, cyano, and nitro;
J is selected from the group consisting of O, S, CH2, CHR6, C(R6)2, NH, and NR6;
R4 is selected from the group consisting of H, S(O)R7, SO2R7, CH2OC(O)xe2x80x94R7, and C(O)xe2x80x94R7 where C(O)xe2x80x94R7 represents natural or synthetic amino acids or R7 is defined as below, or R4 and R3 taken together comprise a 5- or 6-membered heterocyclic ring containing two or more heteroatoms, optionally substituted with alkyl or oxygen functions or both, including carbonyl, or taken together comprise a metal complex containing a divalent cation, or a boron complex;
R5 is R6 or C(O)xe2x80x94R6;
R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, and aryl, all optionally substituted by one or more alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, nitro, cyano, or amino groups;
R7 is selected from the group consisting of substituted dihydropyridyl, alkyl, thioalkoxy, alkoxy, amino, and cycloalkoxy, all optionally substituted with one or more of amino, alkyl, alkylaryl, heterocycle, alkylheterocycle, alkylmercaptoalkyl, which may optionally be substituted with one or more of hydroxy, amino, guanidino, iminoalkyl;
L is selected from the group consisting of lower alkylenes, lower alkenylenes and lower alkynylenes, which may optionally be substituted by one or more alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, or amino groups; or
L is selected from the group consisting of the formula xe2x80x94(CH2)kQ(CH2)txe2x80x94 where k is 1, 2 or 3, t is 1, 2 or 3 and Q is O, Se, Se(O)g, SiE2 where E is lower alkyl, aryl, S(O)g where g is 0, 1 or 2, or NR; or
L is selected from the group consisting of the formula xe2x80x94(CH2)mT(CH2)nxe2x80x94 where m is 0, 1 or 2, n is 0, 1 or 2, T is a 3 to 6 membered carbocyclic or heterocyclic ring or aromatic ring which may optionally be substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halogen, nitro, cyano, trifluoroalkyl and amino;
X is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R6)2, S(xe2x95x90O), SO2, and C(R6)2;
Y is a bond or is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R6)2, S(xe2x95x90O), SO2, and C(R6)2;
Z is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R6)2, S(xe2x95x90O), SO2, and C(R6)2.
It is an object of the present invention to provide compounds that have usefulness as inhibitors of nitric oxide synthase. These compounds also preferentially inhibit the inducible form over a constitutive form.
Compounds of the present invention are represented by the following chemical formula: 
and pharmaceutically acceptable salts, wherein:
A is O, S, or NR, wherein:
R is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, alkylaryl, alkylheterocycle, all optionally substituted by one or more of alkyl, hydroxy, alkoxy, halogen, haloalkyl, cyano, amino, nitro; or
NR together form a heterocycle;
R1 is not present or is selected from the group consisting of hydrogen, lower alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocycle, aryl, alkylaryl, and alkylheterocycle, all optionally substituted by one or more of alkyl, hydroxy, alkoxy, halogen, haloalkyl, cyano, amino, and nitro;
R2 is selected from the group consisting of amino, thioalkoxy, alkoxy, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, aryl, heterocycle, alkylaryl, alkylheterocycle, alkoxyalkyl, and thioalkoxyalkyl all optionally substituted by one or more of alkyl, hydroxy, alkoxy, halogen, haloalkyl, cyano, amino, and nitro;
R3 is not present or is selected from the group consisting of H, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycle, alkylaryl, and alkylheterocycle, all optionally substituted by one or more of halogen, haloalkyl, cyano, nitro, xe2x80x94CO2R, and xe2x80x94COR; or
R3 is selected from the group consisting of alkylhydroxy, alkylpolyhydroxy, alkyl(poly)oxyacyl, CH2C(xe2x95x90O)OR6, CH2C(xe2x95x90O)NHR6, CH2OC(xe2x95x90O)R6, and CH2OC(xe2x95x90O)JR6, the CH2 is optionally substituted by one or more of lower alkyl, cycloalkyl, heterocycle, aryl, amidino, guanidino, CO2H, amino, hydroxy, thiol, halogen, haloalkyl, cyano, and nitro;
J is selected from the group consisting of O, S, CH2, CHR6, C(R6)2, NH, and NR6;
R4 is selected from the group consisting of H, S(O)R7, SO2R7, CH2OC(O)xe2x80x94R7, and C(O)xe2x80x94R7 where C(O)xe2x80x94R7 represents natural or synthetic amino acids or R7 is defined below, or R4 and R3 taken together comprise a 5- or 6-membered heterocyclic ring containing two or more heteroatoms, optionally substituted with alkyl or oxygen functions or both, including carbonyl, or taken together comprise a metal complex containing a divalent cation, or a boron complex;
R5 is R6 or C(O)xe2x80x94R6;
R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, and aryl, all optionally substituted by one or more alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, nitro, cyano, or amino groups;
R7 is selected from the group consisting of substituted dihydropyridyl, alkyl, thioalkoxy, alkoxy, amino, and cycloalkoxy, all optionally substituted with one or more of amino, alkyl, alkylaryl, heterocycle, alkylheterocycle, and alkylmercaptoalkyl, which may optionally be substituted with one or more of hydroxy, amino, guanidino, and iminoalkyl;
L is selected from the group consisting of lower alkylenes, lower alkenylenes and lower alkynylenes which may optionally be substituted by one or more and alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, or amino groups; or
L is selected from the group consisting of the formula xe2x80x94(CH2)kQ(CH2)txe2x80x94 where k is 1, 2 or 3, t is 1, 2 or 3 and Q is O, Se, Se(O)g, SiE2 where E is lower alkyl, aryl, S(O)g where g is 0, 1 or 2, or NR; or
L is selected from the group consisting of the formula xe2x80x94(CH2)mT(CH2)nxe2x80x94 where m is 0, 1 or 2, n is 0, 1 or 2, T is a 3 to 6 membered carbocyclic or heterocyclic ring, or aromatic ring which may optionally be substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halogen, nitro, cyano, trifluoroalkyl and amino;
X is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R6)2, S(xe2x95x90O), SO2, and C(R6)2;
Y is a bond or is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R6)2, S(xe2x95x90O), SO2, and C(R6)2;
Z is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R6)2, S(xe2x95x90O), SO2, and C(R6)2.
A preferred embodiment of the present invention is a compound of the formula (I) and pharmaceutically acceptable salts, wherein:
A is O, S, or NR, wherein:
R is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl,-alkylaryl, and alkylheterocycle, all optionally substituted by one or more of alkyl, hydroxy, alkoxy, halogen, haloalkyl, cyano, amino, and nitro; or
NR together form a heterocycle;
R1 is not present or is selected from the group consisting of hydrogen, lower alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocycle, aryl, alkylaryl, and alkylheterocycle, all optionally substituted by one or more of alkyl, hydroxy, alkoxy, halogen, haloalkyl, cyano, amino, and nitro;
R2 is selected from the group consisting of amino, thioalkoxy, alkoxy, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, aryl, heterocycle, alkylaryl, alkylheterocycle, alkoxyalkyl, and thioalkoxyalkyl all optionally substituted by one or more of alkyl, hydroxy, alkoxy, halogen, haloalkyl, cyano, amino, and nitro;
R3 is not present or is selected from the group consisting of H, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycle, alkylaryl, and alkylheterocycle, all optionally substituted by one or more of halogen, haloalkyl, cyano, nitro, xe2x80x94CO2R, and xe2x80x94COR; or
R3 is selected from the group consisting of alkylhydroxy, alkylpolyhydroxy, alkyl(poly)oxyacyl, CH2C(xe2x95x90O)OR6, CH2C(xe2x95x90O)NHR6, CH2OC(xe2x95x90O)R6, and CH2OC(xe2x95x90O)JR6, the CH2 is optionally substituted by one or more of lower alkyl, cycloalkyl, heterocycle, aryl, amidino, guanidino, CO2H, amino, hydroxy, thiol, halogen, haloalkyl, cyano, and nitro;
J is selected from the group consisting of O, S, CH2, CHR6, C(R6)2, NH, and NR6;
R4 is selected from the group consisting of H, S(O)R7, SO2R7, CH2OC(O)xe2x80x94R7, and C(O)xe2x80x94R7 where C(O)xe2x80x94R7 represents natural or synthetic amino acids or R7 is defined as below, or R4 and R3 taken together comprise a 5- or 6-membered heterocyclic ring containing two or more heteroatoms, optionally substituted with alkyl or oxygen functions or both, including carbonyl, or taken together comprise a metal complex containing a divalent cation, or a boron complex;
R5 is R6 or C(O)xe2x80x94R6;
R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, and heterocycle, and aryl, all optionally substituted by one or more alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, nitro, cyano, or amino groups;
R7 is selected from the group consisting of substituted dihydropyridyl, alkyl, thioalkoxy, alkoxy, amino, and cycloalkoxy, all optionally substituted with one or more of amino, alkyl, alkylaryl, heterocycle, alkylheterocycle, and alkylmercaptoalkyl, which may optionally be substituted with one or more of hydroxy, amino, guanidino, and iminoalkyl;
L is selected from the group consisting of lower alkylenes, lower alkenylenes and lower alkynylenes which may optionally be substituted by one or more alkyl, alkoxy, hydroxy, halogen, trifluoromethyl, nitro, cyano, or amino groups; or
L is selected from the group consisting of the formula xe2x80x94(CH2)kQ(CH2)txe2x80x94 where k is 1, 2 or 3, t is 1, 2 or 3 and Q is O, Se, Se(O)g, SiE2 where E is lower alkyl, aryl, S(O)g where g is 0, 1 or 2, or NR; or
L is selected from the group consisting of the formula xe2x80x94(CH2)mT(CH2)nxe2x80x94 where m is 0, 1 or 2, n is 0, 1 or 2, T is a 3 to 6 membered carbocyclic or heterocyclic ring, or aromatic ring which may optionally be substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halogen, nitro, cyano, trifluoroalkyl and amino;
X is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R6)2, S(xe2x95x90O), SO2, and C(R6)2;
Y is a bond or is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R6)2, S(xe2x95x90O), SO2, and C(R6)2;
Z is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R6)2, S(xe2x95x90O), SO2, and C(R6)2.
A further preferred embodiment of the present invention is a compound of the formula (I) and pharmaceutically acceptable salts, wherein:
A is O, S, or NR, wherein:
R is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, alkylaryl, and alkylheterocycle, all optionally substituted by one or more of alkyl, hydroxy, cyano, amino, nitro; or
NR together form a heterocycle;
R1 is not present or is selected from the group consisting of hydrogen, lower alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocycle, aryl, alkylaryl, and alkylheterocycle;
R2 is selected from the group consisting of amino, thioalkoxy, alkoxy, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, aryl, heterocycle, alkylaryl, alkylheterocycle, alkoxyalkyl, and thioalkoxyalkyl all optionally substituted by one or more of alkyl, hydroxy, cyano, amino, and nitro;
R3 is not present or is selected from the group consisting of H, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycle, alkylaryl, and alkylheterocycle, all optionally substituted by one or more of cyano, nitro, xe2x80x94CO2R, and xe2x80x94COR; or
R3 is selected from the group consisting of CH2C(xe2x95x90O)OR6, CH2C(xe2x95x90O)NHR6, CH2OC(xe2x95x90O)R6, and CH2OC(xe2x95x90O)JR6, the CH2 is optionally substituted by one or more of lower alkyl, cycloalkyl, heterocycle, aryl, amidino, guanidino, CO2H, amino, hydroxy, thiol, halogen, haloalkyl, cyano, and nitro;
J is selected from the group consisting of O, S, CH2, CHR6, C(R6)2, NH, and NR6;
R4 is selected from the group consisting of H, S(O)R7, SO2R7, CH2OC(O)xe2x80x94R71 and C(O)xe2x80x94R7 where C(O)xe2x80x94R7 represents natural or synthetic amino acids or R7 is defined as below, or R4 and R3 taken together comprise a 5- or 6-membered heterocyclic ring containing two or more heteroatoms;
R5 is R6 or C(O)xe2x80x94R6;
R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, and aryl, all optionally substituted by one or more alkyl, hydroxy, nitro, cyano, and amino groups;
R7 is selected from the group consisting of substituted dihydropyridyl, alkyl, thioalkoxy, alkoxy, amino, and cycloalkoxy, all optionally substituted with one or more of amino, alkyl, alkylaryl, heterocycle, alkylheterocycle, and alkylmercaptoalkyl, which may optionally be substituted with one or more of hydroxy, amino, guanidino, and iminoalkyl;
L is selected from the group consisting of lower alkylenes, lower alkenylenes and lower alkynylenes which may optionally be substituted by one or more alkyl, hydroxy, nitro, cyano, and amino groups; or
L is selected from the group consisting of the formula xe2x80x94(CH2)kQ(CH2)txe2x80x94 where k is 1, 2 or 3, t is 1, 2 or 3 and Q is O, Se, Se(O)g, SiE2 where E is lower alkyl, aryl, S(O)g where g is 0, 1 or 2, or NR; or
L is selected from the group consisting of the formula xe2x80x94(CH2)mT(CH2)nxe2x80x94 where m is 0, 1 or 2, n is 0, 1 or 2, T is a 3 to 6 membered carbocyclic or heterocyclic ring, or aromatic ring which may optionally be substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halogen, nitro, cyano, trifluoroalkyl and amino;
X is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R6)2, S(xe2x95x90O), SO2, and C(R6)2;
Y is a bond or is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R6)2, S(xe2x95x90O), SO2, and C(R6)2;
Z is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R6)2, S(xe2x95x90O), SO2, and C(R6)2.
Another preferred embodiment of the present invention is a compound of the formula (I) and pharmaceutically acceptable salts; wherein:
A is O, S, or NR, wherein:
R is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aryl, alkylaryl, alkylheterocycle; or
NR together form a heterocycle;
R1 is not present or is hydrogen or lower alkyl;
R2 is selected from the group consisting of amino, thioalkoxy, alkoxy, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, aryl, heterocycle, alkylaryl, alkylheterocycle, alkoxyalkyl, and thioalkoxyalkyl all optionally substituted by one or more of alkyl, hydroxy, cyano, amino, and nitro;
R3 is not present or is selected from the group consisting of H, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aryl, heterocycle, alkylaryl, and alkylheterocycle, all optionally substituted by one or more of xe2x80x94CO2R, and xe2x80x94COR; or
R3 is selected from the group consisting of CH2C(xe2x95x90O)OR6, CH2C(xe2x95x90O)NHR6, CH2OC(xe2x95x90O)R6, and CH2OC(xe2x95x90O)JR6, the CH2 is optionally substituted by one or more of lower alkyl, cycloalkyl, heterocycle, aryl, amidino, guanidino, CO2H, amino, hydroxy, thiol, halogen, haloalkyl, cyano, and nitro;
J is O, S, or NH;
R4 is H, CH2OC(O)xe2x80x94R7, or C(O)xe2x80x94R7 
R5 is R6 or C(O)xe2x80x94R6;
R6 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, and aryl;
R7 is selected from the group consisting of substituted dihydropyridyl, alkyl, thioalkoxy, alkoxy, amino, and cycloalkoxy, all optionally substituted with one or more of amino, alkyl, alkylaryl, heterocycle, alkylheterocycle, alkylmercaptoalkyl, which may optionally be substituted with one or more of hydroxy, amino, guanidino, and iminoalkyl;
L is selected from the group consisting of lower alkylenes and lower alkenylenes which may optionally be substituted by one or more alkyl, hydroxy, nitro, cyano, or amino groups; or
L is selected from the group consisting of the formula xe2x80x94(CH2)kQ(CH2)txe2x80x94 where k is 1, 2 or 3, t is 1, 2 or 3 and Q is O, Se, Se(O)g, SiE2 where E is lower alkyl, aryl, S(O)g where g is 0, 1 or 2, or NR; or
L is selected from the group consisting of the formula xe2x80x94(CH2)mT(CH2)nxe2x80x94 where m is 0, 1 or 2, n is 0, 1 or 2, T is a 3 to 6 membered carbocyclic or heterocyclic ring, or aromatic ring which may optionally be substituted by one or more substituents selected from the group consisting of lower alkyl, lower alkoxy, hydroxy, halogen, nitro, cyano, trifluoroalkyl and amino;
X is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R6)2, S(xe2x95x90O), SO2, and C(R6)2;
Y is a bond or is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R6)2, S(xe2x95x90O), SO2, and C(R6)2;
Z is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R6)2, S(xe2x95x90O), SO2, and C(R6)2.
Another preferred embodiment of the present invention is a compound of the formula (I) and pharmaceutically acceptable salts; wherein:
A is O or NR;
R is selected from the group consisting of heterocycle, aryl, alkylaryl, and alkylheterocycle;
R1 is hydrogen;
R2 is selected from the group consisting of amino, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, haloalkyl, aryl, heterocycle, alkylaryl, alkylheterocycle, alkoxyalkyl, and thioalkoxyalkyl;
R3 is not present or is selected from the group consisting of H, lower alkyl, aryl, heterocycle, alkylaryl, and alkylheterocycle; or
R3 is CH2C(xe2x95x90O)OR6 or CH2C(xe2x95x90O)NHR6, the CH2 is optionally substituted by one or more of lower alkyl, cycloalkyl, heterocycle, aryl, amidino, guanidino, CO2H, amino, hydroxy, thiol, halogen, haloalkyl, cyano, and nitro;
R4 is H, CH2OC(O)xe2x80x94R7 or C(O)xe2x80x94R7;
R5 is R6 or C(O)xe2x80x94R6;
R6 is hydrogen, alkyl, heterocyclic, or aryl, or;
R7 is alkyl, optionally substituted with one or more of amino, alkyl, alkylaryl, heterocycle, alkylheterocycle, alkylmercaptoalkyl, hydroxy, guanidino, and iminoalkyl;
L is selected from the group consisting of lower alkylenes and lower alkenylenes; or
L is selected from the group consisting of the formula xe2x80x94(CH2)kQ(CH2)txe2x80x94 where k is 1, 2 or 3, t is 1, 2 or 3 and Q is O, Se, Se(O)g, SiE2 where E is lower alkyl, aryl, S(O)g where g is 0, 1 or 2, or NR where R is H or lower alkyl; or
L is selected from the group consisting of the formula xe2x80x94(CH2)mT(CH2)nxe2x80x94 where m is 0, 1 or 2, n is 0, 1 or 2, T is a 3 to 6 membered carbocyclic ring, heterocyclic ring, or aromatic ring;
X is O, S, or C(xe2x95x90O );
Y is a bond or is O, S, or C(xe2x95x90O );
Z is O, S, or C(xe2x95x90O).
Another preferred embodiment of the present invention is a compound of the formula (I) and pharmaceutically acceptable salts; wherein:
A is O ;
R1 is hydrogen;
R2 is lower alkyl;
R3 is hydrogen or a lower alkyl having 1 to 4 carbon atoms;
R4 is hydrogen;
R5 is hydrogen;
L is an alkylene having 3 to 5 carbon atoms;
X is O ;
Y is a bond;
Z is C(xe2x95x90O).
The present invention includes compounds of formula (I) in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulphuric, citric, tartaric, phosphoric, lactic, pyruvic, acetic, succinic, oxalic, fumaric, maleic, oxaloacetic, methanesulphonic, ethanesulphonic, xcfx81-toluenesulphonic, benzenesulphonic and isethionic acids. Salts of the compounds of formula (I) can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.
While it may be possible for the compounds of formula (I) to be administered as the raw chemical, it is preferable to present them as a pharmaceutical composition. According to a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof (xe2x80x9cactive ingredientxe2x80x9d) with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be-made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavoured basis such as sucrose and acacia or tragacanrth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
Preferred unit dosage formulations are those containing an effective dose, as-hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.
The compounds of the invention may be administered orally or via injection at a dose of from 0.001 to 2500 mg/kg per day. The dose range for adult humans is generally from 0.005 mg to 10 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
The compounds of formula (I) are preferably administered orally or by injection (intravenous or subcutaneous). The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sexy of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.
As utilized herein, the term xe2x80x9clower alkylxe2x80x9d, alone or in combination, means an acyclic alkyl radical containing from 1 to about 10, preferably from 1 to about 8 carbon atoms and more preferably 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
The term xe2x80x9clower alkenylxe2x80x9d refers to an unsaturated acyclic hydrocarbon radical in so much as it contains at least one double bond. Such radicals containing from about 2 to about 10 carbon atoms, preferably from about 2 to about 8 carbon atoms and more preferably 2 to about 6 carbon atoms. Examples of suitable alkenyl radicals include propylenyl, buten-1-yl, isobutenyl, penten-1-yl, 2-2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.
The term xe2x80x9clower alkynylxe2x80x9d refers to an unsaturated acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 2 to about 8 carbon atoms and more preferably having 2 to about 6 carbon atoms. Examples of suitable alkynyl radicals include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.
The term xe2x80x9cheterocyclic or heterocyclexe2x80x9d means a saturated or unsaturated cyclic hydrocarbon radical with 4 to about 10 carbon atoms, preferably about 5 to about 6; wherein 1 to about 3 carbon atoms are replaced by nitrogen, oxygen or sulfur. The xe2x80x9cheterocyclic radicalxe2x80x9d may be fused to an aromatic hydrocarbon radical. Suitable examples include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, thiazolyl, imidazolyl, indolyl, thiophenyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, 2-imidazonlinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thidmorpholinyl, pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl, quinolinyl, and the like.
The term xe2x80x9carylxe2x80x9d means an aromatic hydrocarbon radical of 6 to about 14 carbon atoms, preferably 6 to about 10 carbon atoms. Examples of suitable aromatic hydrocarbon radicals include phenyl, naphthyl, and the like.
The terms xe2x80x9ccycloalkylxe2x80x9d or xe2x80x9ccycloalkenylxe2x80x9d means an alicyclic radical in a ring with 3 to about 10 carbon atoms, and preferably from 3 to about 6 carbon atoms. Examples of suitable alicyclic radicals include cyclopropyl, cyclopropenyl, cyclobutyl, cyclopentyl, cyclohexyl, 2-cyclohexen-1-ylenyl, cyclohexenyl and the like.
The term xe2x80x9calkoxyxe2x80x9d, alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above and most preferably containing 1 to about 4 carbon atoms. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
The terms xe2x80x9clower alkylenexe2x80x9d, xe2x80x9clower alkenylenexe2x80x9d and xe2x80x9clower alkynylenexe2x80x9d refers to hydrocarbons containing 2 to 10 carbon atoms, preferably 2 to 8 carbon atoms, and more preferably 2 to 6 carbon atoms.
The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine or iodine.
The term xe2x80x9chaloalkylxe2x80x9d, means an alkyl radical as defined above, with halogen radicals replacing one or more of the hydrogens.
The term xe2x80x9cprodrugxe2x80x9d refers to a compound that is made more active in vivo.
As used herein, reference to xe2x80x9ctreatmentxe2x80x9d of a patient is intended to include prophylaxis.
All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein.
The following general synthetic sequences are useful in making the present invention. 
Without further elaboration, it is believed that one skilled in the art can, using the preceeding description, utilize the present invention to its fullest extent. Therefore the following preferred specific embodiments are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever.
All experiments were performed under either dry nitrogen or argon. All solvents and reagents were used without further purification unless otherwise noted. The routine work-up of the reactions involved the addition of the reaction mixture to a mixture of either neutral, or acidic, or basic aqueous solutions and organic solvent. The aqueous layer was extracted n times (x) with the indicated organic solvent. The combined organic extracts were washed n times (x) with the indicated aqueous solutions, dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified as indicated. Separations by column chromatography were achieved with conditions described by Still. (Still, W. C.; Kahn, M.; Mitra, A. Rapid Chromatograhic Technique for Preparative Separation with Moderate Resolution. J. Org. Chem., 1978, 43, 2923-2925.) The hydrochloride salts were made from 1N HCl, HCl in ethanol (EtOH), 2 N in MeOH, or 6 N HCl in dioxane. Thin layer chromatograms were run on 0.25 mm EM precoated plates of silica gel 60 F254. High performance liquid chromatograms (HPLC) were obtained from C-8 or C-18 reverse phase columns which were obtained from several vendors. Analytical samples were dried in an Abderhalden apparatus at either 56xc2x0 C. or 78xc2x0 C. 1H NMR spectra were obtained from either General Electric QE-300 or Varian VXR 400 MHz spectrometers with tetramethylsilane as an internal standard. 13C NMR spectra were obtained from a Varian spectrometer at 125.8 MHz with tetramethylsilane as an internal standard.